Animals such as mammals and birds are often susceptible to parasite infestations/infections. These parasites may be ectoparasites, such as insects, and endoparasites such as filariae and other worms. Domesticated animals, such as cats and dogs, are often infested with one or more of the following ectoparasites:                fleas (Ctenocephalides spp., such as Ctenocephalides felts and the like),        ticks (Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyoma spp., and the like),        mites (Demodex spp., Sarcoptes spp., Otodectes spp., and the like),        lice (Trichodectes spp., Cheyletiella spp., Lignonathus spp. and the like),        mosquitoes (Aedes spp., Culux spp., Anopheles spp. and the like) and        flies (Hematobia spp., Musca spp., Stomoxys spp., Dematobia spp., Coclyomia spp. and the like).        
Fleas are a particular problem because not only do they adversely affect the health of the animal or human, but they also cause a great deal of psychological stress. Moreover, fleas are also vectors of pathogenic agents in animals, such as dog tapeworm (Dipylidium caninum), and humans.
Similarly, ticks are also harmful to the physical and psychological health of the animal or human. However, the most serious problem associated with ticks is that they are the vector of pathogenic agents in both humans and animals. Major diseases which are caused by ticks include borrelioses (Lyme disease caused by Borrelia burgdorferi), babesioses (or piroplasmoses caused by Babesia spp.) and rickettsioses (also known as Rocky Mountain spotted fever). Ticks also release toxins which cause inflammation or paralysis in the host. Occasionally, these toxins are fatal to the host.
Moreover, mites and lice are particularly difficult to combat since there are very few active substances which act on these parasites and they require frequent treatment.
Likewise, farm animals are also susceptible to parasite infestations. For example, cattle are affected by a large number of parasites. A parasite which is very prevalent among farm animals is the tick genus Boophilus, especially those of the species microplus (cattle tick), decoloratus and annulatus. Ticks, such as Boophilus microplus, are particularly difficult to control because they live in the pasture where farm animals graze. Other important parasites of cattle and sheep are listed as follows:                myiases-causing flies such as Dermatobia hominis (known as Berne in Brazil) and Cochlyomia hominivorax (greenbottle); sheep myiases-causing flies such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand and South Africa). These are flies whose larva constitutes the animal parasite;        flies proper, namely those whose adult constitutes the parasite, such as Haematobia irritans (horn fly);        lice such as Linognathus vitulorum, etc.; and        mites such as Sarcoptes scabiei and Psoroptes ovis.         
1-arylpyrazoles as a class of chemicals are well known in the art, and certain compounds in this class have been found to be potently active against a wide range of pests and parasites that are harmful to animals and plants. For example, 1-arylpyrazole derivatives are known in the art to prevent, treat or control ectoparasitic infestations in mammals, such as cats, dogs and cattle. Certain 1-arylpyrazoles and their use against pests are described in U.S. Pat. Nos. 4,963,575; 5,122,530; 5,232,940; 5,236,938; 5,246,255; 5,547,974; 5,567,429; 5,576,429; 5,608,077; 5,714,191; 5,814,652; 5,885,607; 5,567,429; 5,817,688; 5,885,607; 5,916,618; 5,922,885; 5,994,386; 6,001,384; 6,010,710; 6,057,355; 6,069,157; 6,083,519; 6,090,751; 6,096,329; 6,124,339; 6,180,798; 6,335,357; 6,350,771; 6,372,774; 6,395,906; 6,413,542; 6,685,954; and 7,468,381, 7,514,561, 7,517,877, 7,759,381 and 7,834,003. See also: EP 0 234 119, EP 0 295 117, EP 0 352 944, EP 0 500 209, EP 0 780 378, EP 0 846 686, and EP 0 948 485, all of which are incorporated herein by reference in their entirety.
The compounds of the families defined in these patents are extremely active and one of these compounds, 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole, or fipronil, is particularly effective against pests, including fleas and ticks.
U.S. Pat. No. 7,759,381 describes certain 1-arylpyrazole compounds that are substituted at the 5-position of the pyrazole ring with alkyl or C1-C4 haloalkyl groups. These compounds were also found to be particularly effective against fleas and ticks.
These compounds are given as having activity against a very large number of parasites, including insects and acarines in fields as varied as agriculture, public health and veterinary medicine. The general teaching of these documents indicates that these active compounds may be administered via different routes: oral, parenteral, percutaneous and topical routes. Topical administration comprises, in particular, skin solutions (pour-on or spot-on), sprays, drenches, baths, showers, jets, powders, greases, shampoos, creams, etc. The pour-on type skin solutions may be designed for percutaneous administration.
Notwithstanding the effectiveness of certain arylpyrazole compounds on certain parasites, there continues to be a need for new formulations comprising 1-arylpyrazoles in pharmaceutically acceptable carriers that exhibit improved efficacy against parasites.
Other compounds that are known in the art to prevent, treat or control endo- and ectoparasitic infestations include milbemycin or avermectin derivatives, which are natural or semi-synthetic compounds that contain a 16-membered macrocyclic ring. The avermectin and milbemycin series of compounds are potent anthelmintic and antiparasitic agents against a wide range of internal and external parasites. The natural product avermectins are disclosed in U.S. Pat. No. 4,310,519 to Albers-Schonberg, et al., and the 22,23-dihydro-avermectin compounds are disclosed in Chabala, et al., U.S. Pat. No. 4,199,569. For a general discussion of avermectins, which include a discussion of their uses in humans and animals, see “Ivermectin and Abamectin,” W. C. Campbell, ed., Springer-Verlag, New York (1989). Naturally occurring milbemycins are described in Aoki et al., U.S. Pat. No. 3,950,360.
Another family of parasiticides are the formamidines which include but are not limited to amitraz (MITABAN®, Pfizer; POINT-GUARD®, Intervet; PREVENTIC®, Virbac; TAKTIC®, Intervet), chlordimeform, chloromebuform, formetanate and formparanate. Amitraz is a well-known acaracide/insecticide from the formamidine family acknowledged to be useful as a miticidal agent and for the control of ticks. See Plumb's Veterinary Drug Handbook (Fifth Edition), ed. Donald C. Plumb, Blackwell Publishing, pg. 34, (2005). The formamidine family of compounds is distinguished by a characteristic —N═CR—NR′-moiety. Amitraz differs from other members of the formamidine family in that there are two such moieties in the molecule. Amitraz has the following structure:

One problem associated with compositions comprising formamidine compounds, including amitraz, is the lack of long-term stability under certain conditions. For example, amitraz has been shown to degrade in aqueous solutions at certain pH ranges, as described, for example, in E. Corta, A. Bakkali, L. A. Berrueta, B. Gallo, F. Vicente, “Kinetics and Mechanism of Amitraz Hydrolysis in Aqueous Media by HPLC and GC-MS”, Talanta 48 (1999) 189-199. Some amitraz degradates have further shown pesticidal efficacy, such as described, for example, in Osborne, M. P., “Actions of Formamidines, Local Anesthetics, Octopamine and Related Compounds Upon the Electrical Activity of Neurohaemal Organs of the Stick Insect (Carausius morosus) and Sense Organs of Fly Larvae (Musca demstica, Calliphora erythrocephala)”, Pesticide Biochemistry and Physiology 23, 190-204 (1985).
Therefore, although formamidine parasiticides, including amitraz, have considerable utility for treating and preventing parasitic infestations, there are several problems associated with using amitraz as a parasiticide in a commercial veterinary pharmaceutical product. These problems include: (1) insufficient stability at certain pH values: while amitraz is stable at higher pH values, amitraz tends to hydrolyze over time at pH ranges commonly associated with physiological use (e.g., pH of about 5.0 to about 6.0); (2) amitraz is not effective for the control of fleas; and (3) compositions comprising amitraz may not provide a sufficiently long term shelf life in mixtures with some antiparisitic agents and certain carriers. For example, compositions containing amitraz may not have sufficient long term stability (shelf life) in certain solvent systems which are optimal for other antiparasitic agents with which it may be combined.
A composition comprising a 1-aryl-pyrazole with a formamidine compound, e.g. fipronil with amitraz, which exhibits synergistic efficacy against ectoparasites is described in U.S. Pat. No. 7,531,186 to Boeckh et al.; however certain embodiments of the composition, where a 1-arylpyrazole and a formamidine are present together in certain carriers, may not have a sufficiently long storage shelf life. One possible reason for the insufficient long term shelf life is that fipronil is stable at a pH of about 5.0 to about 6.0, while amitraz will degrade at this pH range.
Interestingly, another family of compounds generally known as substituted imidazoles has been shown to have modest insecticidal activity. This class of compounds is also known for activity at alpha-1 and alpha-2 adrenergic receptors. See, e.g., Whitlock et al., Bioorganic & Medicinal Chemistry Letters, 18, (2008), 2930-2934 and Whitlock et al., Bioorganic & Medicinal Chemistry Letters, 19, (2009), 3118-3121 regarding partial agonist activity of substituted imidazoles at alpha-1A adrenoceptors.
U.S. Pat. No. 7,417,057 and its divisional U.S. Pat. No. 7,767,667 to Dixson et al., disclose pesticidal heterocycles that include imidazole derivatives. The pesticidal heterocycles of the '057 and '667 patents were demonstrated to be moderately active against cotton aphids at high concentration (300 ppm for 24 hours).
U.S. Pat. No. 7,592,362 and its divisional U.S. Pat. No. 7,825,149 to Chubb et al., disclose hundreds of imidazole compounds that are reportedly useful as paraciticides although no data in the patents show this.
WO 2010/020896 to Chubb et al., discloses a combination of an alpha substituted 2-benzyl substituted imidazole, a 1-arylpyrazole (e.g., fipronil), and optionally an insect growth regulator (e.g., s-methoprene). Tested in vivo formulations demonstrated some efficacy against C. felis (i.e., cat fleas) out to 35 days and against I. ricinus (i.e., castor bean tick) out to day 28.
WO 2011/092604 to Chubb et al., discloses a combination of demiditraz, fipronil, an acid modifier, and optionally at least one antioxidant.
Despite the work done to date synthesizing compounds to control parasites, there remains a need in the art for formulations, methods of storage and methods of administration for animal parasiticides in a synergistically active formulation.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.